Abstract
TRAF family member-associated NF-κB activator (TANK) is a negative regulator of canonical NF-κB signaling in the Toll-like receptor- and B-cell receptor-mediated signaling pathways. However, functions of TANK in viral infection-mediated NF-κB activation remain unclear. Here, we reported that TANK was cleaved by encephalomyocarditis virus 3C at the 197 and 291 glutamine residues, which depends on its cysteine protease activity. In addition, encephalomyocarditis virus 3C impaired the ability of TANK to inhibit TRAF6-mediated NF-κB signaling. Interestingly, we found that several viral proteases encoded by the foot and mouth disease virus, porcine reproductive and respiratory syndrome virus, and equine arteritis virus also cleaved TANK. Our results suggest that TANK is a novel target of some viral proteases, indicating that some positive RNA viruses have evolved to utilize their major proteases to regulate NF-κB activation.
Highlights
TANK is a negative regulator of canonical NF-B signaling
TANK Is a Novel Target of Encephalomyocarditis virus (EMCV) 3C Protease—Previous studies demonstrated that viral proteases encoded by several picornaviruses could cleave the key molecules in type I interferon (IFN) and NF-B signaling pathways, which resulted in the inhibition of IFN production and NF-B activation (26, 30 –32)
To investigate which host protein related to IFN and NF-B signaling pathways is cleaved by EMCV 3C protease (EMCV 3C), HEK293T cells were transfected with a plasmid ectopically expressing FLAG-tagged RIG-I, MDA5, MAVS, TANK, TBK1, IKK⑀, NEMO, IKK␣, TRAF3, TRAF6, or IRF3, in combination with empty vector or a plasmid expressing HA-EMCV 3C
Summary
TANK is a negative regulator of canonical NF-B signaling. Results: EMCV 3C cleaves TANK and regulates NF-B activation. Significance: TANK is a novel target protein of viral proteases encoded by several positive RNA viruses. TRAF family member-associated NF-B activator (TANK) is a negative regulator of canonical NF-B signaling in the Toll-like receptor- and B-cell receptor-mediated signaling pathways. Because of the important biological functions of NF-B in the innate and adaptive immune responses, the transcriptional activity of nuclear NF-B is tightly regulated through post-translational modifications at multiple levels by positive and negative regulatory elements [20]. We found that other viral proteases encoded by FMDV, PRRSV, and EAV could cleave TANK in vitro, the cleavage sites are different To our knowledge, this is the first report to show that EMCV 3C cleaves TANK in vitro. Our findings reveal that several positive RNA viruses have adopted a novel mechanism to regulate NF-B signaling by cleavage of TANK using their proteases
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